Surgery, radiotherapy and systemic drug therapy are the three main methods of antitumor therapy. While these treatments are essential for cancer management, they can also lead to various complications. Unlike the acute reactions often seen with surgery and systemic drug therapy, the complications associated with radiotherapy can have a different time course, duration, and management approach.Radiotherapy can result in a range of late complications that may occur months to years after the treatment. These late effects can include xerostomia (dry mouth), dysphagia (swallowing difficulties), dysgeusia (taste changes), digestive and absorption dysfunction, as well as bowel issues such as constipation, diarrhea, and incontinence. The occurrence of these late radiotherapy complications can significantly impact the patient's nutritional status, quality of life, and even the overall success of the cancer treatment.Therefore, it is crucial to have a comprehensive understanding of the nutritional management strategies for these late radiotherapy complications. This literature review and evidence-level analysis aims to provide evidence-based guidelines and decision-making support for radiation oncologists, nutrition nurses, clinical dietitians, and other relevant healthcare professionals involved in the nutritional care of patients experiencing late complications after radiotherapy (Fig. 1).
Fig. 1 [Images not available. See PDF.]
Implement a comprehensive nutritional management strategy to address the late complications associated with radiotherapy
Nutritional management of salivary gland injury after radiotherapy (radiation xerostomia)
Radiation xerostomia is a common complication of radiotherapy in patients with head and neck tumors. It is mainly due to the damage of submandibular gland, parotid gland and other glands caused by radiation exposure. The epithelial cells of the glands are exposed to radiation, resulting in a decrease in saliva secretion, resulting in dry mouth [1]. Saliva has antibacterial activity, prevents oral infections, and plays an important role in multiple functions of the upper gastrointestinal tract, including taste, food bolus formation, facilitating chewing, swallowing, and speaking, and lubricating the oropharyngeal and upper esophageal mucosa [2]. At present,there is no effective drug for the treatment of xerostomia, and only the symptoms can be alleviated. For patients with xerostomia, methods including: (1) keeping the mouth well hydrated; (2) avoiding sucrose, carbonated drinks, fruit juices, and water with additives, (3) drinking water regularly; (4) avoiding medications that may worsen dryness, and (5) using a humidifier. Promoting saliva secretion can reduce a series of uncomfortable symptoms caused by xerostomia, thereby effectively alleviating the discomfort of patients. The M cholinergic receptor agonists, pilocarpine and cevimeline, can stimulate glandular secretion. Pilocarpine is an FDA-approved treatment for radiation xerostomia. Cevimeline is a potential drug for xerostomia, which has been shown to be well tolerated in two randomized controlled research trials and increased unstimulated saliva secretion in radiotherapy patients, and further clinical trials are needed to verify [3, 4].
Saliva substitutes are one of the most effective measures to relieve radiation-induced xerostomia, however, they remain in the mouth for only a short time and may trigger allergic reactions in patients [5–8]. An edible saliva substitute, such as an oral moisturizing gel, can improve the patient's swallowing ability as well as relieve xerostomia, due to its buffer contains and neutral pH [9]. Artificial saliva sprays are easy to carry because of their small size [10]. In addition, a hyaluronic acid solution at a certain concentration is similar saliva in terms of viscosity, elastic modulus, and network structure, and has both antibacterial and antioxidant effects, making it a possible saliva substitute.
Hyperbaric oxygen therapy can affect cytokine secretion, induce local angiogenesis, and mobilize stem cells, suggesting its potential role in the treatment of salivary gland dysfunction [11, 12]. Hyperbaric oxygen therapy has been shown to improve patients' dry mouth, taste, and ability to swallow [13–15]. However, most of these studies lack adequate sample sizes and suitable control groups. Its therapeutic effect is controversial due to factors such as the placebo effect and the patient's to xerostomia. The optimal start time and treatment frequency of hyperbaric oxygen therapy after radiotherapy remain to be further studied [16]. In addition, hyperbaric oxygen therapy is expensive and cannot fully restore salivary gland function, so its clinical application is limited.
The decrease of saliva and the change of oral flora after radiotherapy may lead to caries. Long-term follow-up and oral health education should be paid attention to. The management of radiation xerostomia should be carried out throughout the three periods before, during and after radiotherapy, to evaluate patients and take corresponding measures. Multi-disciplinary collaboration is needed to ensure the quality of life of patients.
Nutritional management of masticatory muscle injury (dysphoria) after radiotherapy
Almost all patients undergoing head and neck radiation may have difficult mouth opening after radiotherapy. Because there is no specific treatment means for mouth opening difficulty, the present treatment is mainly to control the progress of limited mouth opening and restoration of motor function. Exercise therapy is generally considered to be the main treatment for lockjaw, and can be used alone or in combination with other methods to achieve better results. can promote the rotation and sliding function of temporomandibular joint, prevent joint stiffness, Exercise therapy also can promote the rotation and sliding function of temporomandibular joint, prevent joint stiffness, promote local blood circulation, relieve masticatory muscle tension, prevent muscle atrophy, and effectively improve local and overall function [17]. There are many ways of exercise but the simplest method is active mandibular movement, including the following steps: opens and closes the mouth repeatedly; Slowly move the lower jaw to the left and then to the right; extend the lower jaw downward, forward and back to the original position. Manipulation treatment can also improve the difficulty of opening mouth after radiotherapy. The research showed that the improvement benefits were greatest after the first manual treatment, and although the gains were small, repeated manual treatment improved oral difficulties better [18]. Forced mouth opening under general anesthesia can improve lockjaw, but the effect is often transient, and can cause alveolar fracture and adjacent soft tissue rupture. A non controlled study has shown that coronectomy is effective in improving refractory trismus in patients with head and neck cancer [19]. Botulinum toxin injection has potential benefits for the treatment of specific complications of radiation fibrosis syndrome. Botulinum toxin injection are potentially beneficial for the treatment of specific complications of radiation fibrotic syndrome. The injection of botulinum toxin into the masseter muscle of patients with head and neck cancer does not relieve the limitation of mouth opening due to radiation fibrosis, but it reduces pain and masticatory spasm [20]. As a part of multimodal therapy, dynamic jaw opening device can effectively improve mouth opening related to head and neck cancer and its treatment [21].
Early treatment is very important to prevent serious and irreversible contracture. Although the evidence is limited, jaw exercises, passive motion devices and splints may be helpful and can be used at an early stage. A randomized controlled trial has shown that three months of rehabilitation training for nasopharyngeal carcinoma patients after radiotherapy can effectively improve mouth opening difficulties [22]. ollow-up of 22 head and neck cancer patients with radiotherapy combined with rehabilitation training for more than 10 years showed that patients' lockjaw status worsened moderately in 6–10 years, and the overall quality of life after surgery was good [23].
Nutrition management of swallowing muscle injury (dysphagia) after radiotherapy
The treatment of dysphagia involves a collaborative effort among doctors, nurses, and therapists, with a focus on four main aspects: nutrition management, swallowing function promotion, compensatory measures, and surgical interventions.
Nutrition is a critical component in the management of patients with dysphagia. Oral feeding, nasogastric tube feeding, or intermittent oral tube feeding should be selected based on the patient's subjective and objective assessment of nutritional and functional status [24]. For patients with severe gastroesophageal reflux, alternative options like gastrojejunal feeding, percutaneous endoscopic gastrostomy, or total parenteral nutrition may be considered. The recommended caloric intake is 25–35 kcal/(kg·day) for stable patients, with adjustments made for severe or unstable cases. Protein supply should be 1–2 g/(kg·day), and water intake should be 30 ml/(kg·day), with modifications as needed. For tube-fed patients, the use of specialized enteral nutrients can help improve energy density and meet target nutritional goals.
Various interventions, such as oral sensory training, oral motor training, airway protection techniques, low-frequency electrical stimulation therapy, surface electromyography biofeedback training, esophageal dilatation, and acupuncture therapy, have been explored to facilitate the restoration of swallowing function. While these approaches have demonstrated promising outcomes in select studies, the necessity for larger, well-designed clinical trials to ascertain their efficacy and optimal application persists [25–27]. Integrating these interventions within a comprehensive treatment plan tailored to individual patient needs is critical for maximizing therapeutic benefits.
Compensatory strategies play a pivotal role in helping patients manage dysphagia symptoms. Approaches like food adjustment, swallowing posture modification, adjustments to eating tools, and modifications to the patient's environment can effectively enhance swallowing function and improve overall quality of life [28, 29]. In cases where patients with severe dysphagia do not respond to conventional rehabilitation or compensatory measures, surgical interventions may be considered as a last resort. Notably, emerging technologies such as neuromuscular electrical stimulation and traditional Chinese medicine acupuncture have showcased promise in dysphagia rehabilitation. However, further research, including larger, well-designed clinical trials, is imperative to fully elucidate the efficacy and safety of these innovative approaches and guide the establishment of evidence-based guidelines for the holistic management of dysphagia.
Nutritional management of taste bud injury (hypogeusia) after radiotherapy
For radiation induced hypogeusia, clinicians should try to prevent the occurrence of such side effects before radiotherapy. The most critical measure is to protect normal organs as much as possible during planning and implementation of radiotherapy. Studies have found that the severity of taste disorders is proportional to the dose of radiation in the mouth and tongue [30].
With the extensive use of intensity modulated radiotherapy (IMRT) in clinical practice, the tumor control and overall survival rate of patients with head and neck squamous cell carcinoma has been tremendously improved. However, with the increase of radiotherapy dose, the incidence of adverse effects has also increased correspondingly [31]. The use of oral filler such as cork can reduce the radiation dose of tongue and salivary gland, so as to reduce the occurrence of side effects such as oral mucositis and hypogeusia. In recent years, with the application of proton/heavy ion radiotherapy, radiation for head and neck tumors can achieve a more accurate effect than photons, greatly reducing the radiation dose of normal tissues and minimizing the related side effects such as taste loss. Studies have confirmed that intensity modulated proton radiotherapy (IMPT) has significantly reduced appetite and taste loss in patients with oropharyngeal cancer compared with IMRT. For the prevention of radiation-related taste loss, the most important measure is to protect the taste buds by reducing the scope and dose of radiation. Two recent studies have shown that the use of chlorhexidine, sodium bicarbonate, and oral irrigation can effectively prevent or ameliorate patients' taste disorders [32, 33].
Taste disorders caused by radiation therapy generally include decreased or disappeared taste,,taste inversion, phantom taste, etc. Because taste is mainly subjective, it is difficult to evaluate and quantify. Nevertheless, patients should be screened for taste disorders before and during radiotherapy to know their taste status in advance. At present, the commonly used clinical taste evaluation methods mainly use different kinds of solutions to determine the patient's taste threshold, and also require the patient to identify different taste types. The commonly used taste disorder screening technologies include: whole mouth test, filter paper disk method, taste measurement method, etc. Studies have found that patients with advanced tumors have varying degrees of smell and taste loss [34].
Diet and drugs are the most common ways to treat radiation-induced taste loss. In terms of diet, avoid eating too much greasy and high-salt food because of the loss of taste function, and it is recommended to eat more food that promotes appetite and saliva secretion to ensure a good nutritional state. In terms of drugs, it can be adjusted by nourishing nerves, supplementing trace elements, promoting appetite and other types of drugs, such as mecobalamine, megestrol, amifostine, and so on. For the clinical treatment of radiation taste disorder, there is no standard protocol at present, and the only treatment that has undergone randomized controlled clinical trials is zinc. A recent meta-analysis, which included studies conducted from 2003 to 2017, found that patients treated with zinc had a lower incidence of radiation-related taste disorders compared with placebo, but the effect of zinc on late restoration of taste was not significant [35].
The recovery of taste usually starts 4–5 weeks after the completion of radiotherapy. It is unclear whether the damage caused by radiation to taste buds caused by radiation is temporary or permanent. It is difficult to quantify the loss and recovery of taste through laboratory examinations. The only certainty is that the degree of taste bud atrophy caused by radiation is related to the dose of exposure to the tongue. The commonly used drug to promote taste recovery of patients after radiation therapy is zinc sulfate, which is usually used after the completion of radiation therapy and is administered continuously for about 4 weeks.. In terms of diet, it is recommended to supplement glutamine,lactoferrin and fish oil to help patients with taste function faster recovery. A study by Wang et al. included 12 patients with taste disorder after chemoradiation and intervention through oral lactoferrin supplementation. The results showed that the patients' taste and olfactory functions were improved one month after lactoferrin supplementation [36].
Nutritional management of gastrointestinal injury (digestive and absorption dysfunction) after radiotherapy
Gastrointestinal injury is a result of radiotherapy to abdominal and pelvic tumors which affects the patient's digestion and absorption function seriously, and results in malnutrition and interruption of treatment. Finally, the gastrointestinal injury affects the patient's prognosis and quality of life. There are evidence indicate that nutrition intervention should be carried out early in malnutrition patients who was gastrointestinal injury. Nutritional support can promote gastrointestinal mucosal repair, maintain normal intestinal flora, and enhance intestinal mucosal barrier protection, so the value of enteral parenteral nutrition support therapy has been widely recognized, but the timing of nutrition therapy and the selection of nutrients need to be further explored. Acute radiation gastrointestinal reactions are associated with the dose of radiation they receive, and the higher the dose, the greater the risk of digestive and absorptive abnormalities, but for most of acute radiation gastrointestinal injuries, symptoms can be improved after aggressive treatment, and a very small proportion of patients may suffer from severe acute gastrointestinal dysfunction in the case of severe complications. Especially those patients diagnosed acute gastrointestinal dysfunction during and after total abdominal and pelvic radiotherapy.
For patients with dysfunction due to acute gastrointestinal injury, ESICM-WGAP [37] recommends starting the lowest dose of enteral nutrition (20 mL/h) according to AGI classification, and then increasing the nutritional dose to 100% of calculated energy in AGI class I patients. In patients with AGI II or AGI III, it is recommended to start with the lowest dose and give other treatments (such as gastrointestinal motogens) according to the symptoms; Enteral nutrition is not recommended for AGI IV patients.
We recommend that the total energy expenditure (TEE) of cancer patients, if not measured individually, be assumed to be similar to healthy subjects and generally 25 ~ 30 kcal/ (kg·d) [38]. But the TEE should be adjusted dynamically according to the tumor burden, stress state and acute radiation injury. In the early stage of malnutrition, it is not required to meet the target demand at the beginning, and low-calorie enteral nutrition may be safer. In the process, patients should be closely monitored for enteral nutrition tolerance, and the feeding speed should be adjusted in time according to the feeding tolerance score.
For patients with digestive and absorptive dysfunction, it is necessary to identify the etiology, location, and purpose of nutritional therapy, and choose appropriate way of nutritional therapy [39]. Patients with simple gastric radiation injury can be considered to undergo jejunostomy. For patients with lower gastrointestinal bleeding, enteral nutrition should be used with caution, and parenteral nutrition therapy can be considered, and digestive bleeding should be actively treated.
For patients with digestive and absorption dysfunction due to radiation therapy, it is important to select a tolerated enteral nutrition formula.. Commonly used enteral nutrition formulations include short peptide type pre-digestion formulations, medium chain triglyceride nutritional formulations and probiotics formulations, etc. Appropriate formulations should be selected according to the patient's age, gender, original diet structure, tumor location, degree of gastrointestinal damage, emergency state, etc.
As intestinal epithelial cells absorb short peptides, the hydrolyzed protein nutrition formula can be applied to severe patients with whole protein intolerance. The medium chain triglyceride nutritional formula can be quickly absorbed by the small intestine, metabolized by the liver, and easily digested. It can improve gastric emptying and partially reduce the secretion of gastrointestinal hormones such as cholecystokinin and glucagon-like peptide—1. In addition, Lactobacillus, as a probiotic and intestinal symbiotic bacteria, is beneficial to intestinal health and can prevent and treat diarrhea caused by radioactive intestinal injury by protecting intestinal crypt stem cells, maintaining intestinal barrier and antioxidant effects. However, further clinical studies are needed on its usage, dosage and duration of administration [40]. In addition, studies have shown that intestinal flora transplantation is an effective means to treat radiation-induced intestinal injury, and can improve intestinal flora disorders, facilitate protein synthesis, and promote carbohydrate absorption [41].
Abdominal pain and dyspepsia can be treated with acid suppressants, including proton pump inhibitors. Patients with severe abdominal pain can use anesthetic and non-anesthetic analgesics according to the "three-step principle". Active surgical intervention should be considered for patients with severe radioactive gastrointestinal injuries, including gastrointestinal ulceration, perforation, bleeding, and co-infection [42]. At the same time, appropriate enteral and parenteral nutrition support treatment should be selected according to the specific conditions of patients.
In the era of precise radiotherapy, the digestive and absorptive functions caused by radiotherapy are mostly mild and short-term,which can be recovered by itself. Some patients may suffer from repeated illness or develop into chronic illness, requiring rehabilitation training and traditional Chinese medicine conditioning, as well as psychological counseling [43].
Nutritional management of rectal and anal sphincter injury (constipation/diarrhea/fecal incontinence) after radiotherapy
The most common late complication of pelvic radiotherapy is anorectal ulcer, with anal stenosis or anorectal fistula also occurring in some cases. These complications often manifest as anal pain and incontinence. While case reports have suggested potential benefits of oral vitamin A and hyperbaric oxygen therapy for radiation-induced anorectal ulcers, there is a lack of large, well-designed controlled trials evaluating the treatment of radiation-induced rectal injuries. The existing evidence on the management of radiation rectal injury primarily comes from case reports and small clinical studies, and there is still no established effective treatment for chronic intestinal injury caused by radiotherapy.
Non-surgical treatment options include probiotics, hormones, non-steroidal anti-inflammatory drugs, antibiotics, and hyperbaric oxygen therapy. These interventions have shown some promising results in case reports and small studies, but their efficacy and safety profiles are yet to be fully elucidated due to the lack of large, high-quality clinical trials. Surgical treatment, endoscopic interventions, and bacterial transplantation are also being explored as potential treatment modalities, though they come with their own set of challenges and risks, such as the need for specialized expertise and the potential for complications [44, 45].
Looking to the future, emerging treatments like glutamine enemas and growth factors that promote intestinal mucosal repair hold promise for improving the management of radiation-induced rectal injuries. The rationale behind these novel approaches is to directly target the underlying mucosal damage and promote healing, potentially offering a more targeted and effective solution compared to the current standard of care. However, further research, including larger, well-designed clinical trials, is needed to establish the efficacy and safety of these emerging interventions and to inform the development of more standardized, evidence-based guidelines for the nutritional management of late radiotherapy complications.
When diarrhea occurs, patients should be advised to avoid high-fiber foods, such as fruits, vegetables, and whole grains, which may exacerbate diarrhea and rapid bowel movements. Instead, they should be encouraged to consume foods with anti-diarrheal effects, such as burnt rice soup, egg yolk rice soup, and carrot puree [46, 47]. A meta-analysis of randomized controlled trials has shown that prophylactic probiotic therapy can be helpful in relieving radiotherapy-induced diarrhea. In severe cases, loperamide 2 mg can be taken, with the dosage adjusted according to the severity. Radiotherapy should be temporarily suspended, and corticosteroid-based hormone therapy may be considered as appropriate. Patients with constipation can be treated with stool softeners, and their dietary fiber intake should be increased through the consumption of vegetables, fruits, and other fiber-rich foods like kelp, bananas, honey, walnuts, and peanuts. Increased water intake, with a recommended daily amount of over 3000 ml, can also help relieve constipation. For patients suffering from pelvic floor muscle injury and fecal incontinence, neuromuscular re-education, biofeedback therapy, and electrical stimulation can be considered to improve pelvic floor muscle strength and coordination. In cases of anal stenosis, anal expansion may be an option, and surgery may be necessary if conservative measures are not effective [48].
Nutrition counseling and nutrition support can significantly improve the nutritional status and quality of life of patients with pelvic tumors undergoing radiotherapy. Parenteral nutrition is recommended for severe diarrhea and intestinal obstruction, but it carries the risk of peripheral or central venous infections. When the patient's condition allows, it is recommended to transition from parenteral to enteral nutrition as soon as possible. The management of radiation-induced rectal and anal sphincter injury requires a multifaceted approach, combining dietary modifications, pharmacological interventions, and specialized therapies [49, 50]. While the current evidence provides some guidance, there is a clear need for larger, well-designed clinical trials to establish more robust, evidence-based strategies for the nutritional management of these late radiotherapy complications. Emerging treatments, such as glutamine enemas and growth factors, hold promise for improving patient outcomes, but further research is required to fully explore their potential.
Summary and outlook
Late complications following radiotherapy exert a substantial influence on the health and survival of patients, underscoring the necessity of an all-encompassing nutritional management strategy. Subsequent studies and clinical applications should concentrate on investigating tailored nutritional management schemes to enhance patients' quality of life and treatment efficacy. Interdisciplinary collaboration and holistic treatment modalities will prove pivotal, and ongoing research endeavors will aid in devising more efficacious interventions to alleviate the adverse repercussions of late radiotherapy complications on patients, ultimately enhancing both survival rates and quality of life.
Authors’ contributions
JHL and TL designed the study. JHL and TL designed the research. YS, HSB, HK and CRL performed the literature review. XMZ, LL (Long Liang), LL (Lu li) and DOC conceived and produced the figure. JHL wrote the manuscript. DOC and TL provided supervision. All authors reviewed the paper. The author(s) read and approved the final manuscript.
Funding
No funding was obtained for this study.
Data availability
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
All authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Publisher’s Note
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Abstract
Late complications of radiotherapy can include a variety of issues, such as xerostomia, dysphagia, taste changes, digestive and absorption dysfunction. These late complications can seriously impact the nutritional status and quality of life of patients following radiotherapy, and may even adversely affect tumor control and patient survival. Comprehensive nutritional management strategies should be implemented to address these late complications. For radiation-induced xerostomia, salivary stimulant drugs, saliva substitutes, and hyperbaric oxygen therapy have demonstrated efficacy in alleviating dry mouth symptoms. The management of post-radiation trismus remains challenging, with functional training, including active jaw exercises, passive motor devices, and splints, being the primary interventions. In the case of radiation-induced dysphagia, a multidisciplinary team approach is recommended, incorporating malnutrition risk assessment, personalized nutritional treatment, nursing care, rehabilitation training, and patient education. Protecting normal organs, such as the tongue and oral cavity, during radiotherapy planning can help prevent and mitigate taste changes, which can be further managed with zinc supplements, oral care, and lactoferrin supplementation. For post-radiation digestive and absorption dysfunction, a comprehensive assessment of the patient's nutritional status, site of gastrointestinal injury, and potential complications (e.g., bleeding, perforation) is crucial in guiding the selection of appropriate nutritional support, ranging from enteral nutrition as the first-line approach to supplemental or even exclusive parenteral nutrition. Surgical intervention may be necessary in some cases. By implementing these multifaceted nutritional management strategies, healthcare professionals can optimize the care of cancer patients undergoing radiotherapy and mitigate the adverse impact of late radiation complications on their overall well-being and treatment outcomes.
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1 Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Radiation Department, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Chengdu, China (GRID:grid.415880.0) (ISNI:0000 0004 1755 2258)